1. Technical Field
The present invention relates to novel urea pyridine compounds which are mineralocorticoid receptor antagonists (also known as aldosterone receptor antagonists), methods for the production of such compounds, the use of such compounds in the treatment of various diseases and pharmaceutical compositions comprising such compounds.
2. Background Information
The mineralocorticoid receptor (often referred to by the abbreviations MR, MLR and MCR) is a nuclear receptor. It is often called the aldosterone receptor because, as explained more fully below, a key activating ligand for this receptor is aldosterone.
Nuclear receptors are a class of proteins found within the interior of cells. They have the ability to directly bind to DNA and regulate the expression of adjacent genes. The regulation of gene expression by a nuclear receptor occurs when a ligand is present and binds to the nuclear receptor. Ligand binding results in a conformational change in the receptor which activates the receptor and brings about regulation of gene expression.
The mineralocorticoid receptor is expressed in many tissues, such as the kidney, colon, heart, central nervous system (hippocampus), brown adipose tissue and sweat glands. In epithelial tissues, its activation leads to the expression of proteins regulating ionic and water transports (mainly the epithelial sodium channel or ENaC, Na+/K+ pump, serum and glucocorticoid induced kinase or SGK1) resulting in the reabsoprtion of sodium, and as a consequence an increase in extracellular volume, increase in blood pressure, and an excretion of potassium to maintain a normal salt concentration in the body.
The receptor is activated by binding to ligands known as mineralocorticoids. These include aldosterone and deoxycorticosterone as well as glucocorticoids, like cortisol and corticosterone. The mineralocorticoid receptor also responds to some progestins.
Increased levels of the mineralocorticoid, aldosterone, are present in primary and secondary hyperaldosteronism. In primary aldosteronism, the adrenal glands produce an excess of aldosterone, causing loss of potassium and retention of sodium. The excess sodium in turn causes water retention, increasing blood volume and blood pressure. Secondary aldosteronism is increased adrenal production of aldosterone in response to nonpituitary, extra-adrenal stimuli. Secondary aldosteronism is caused by reduced renal blood flow, which stimulates the renin-angiotensin mechanism leading to hypersecretion of aldosterone. Causes of reduced renal blood flow include obstructive renal artery disease (eg, atheroma, stenosis), renal vasoconstriction (as occurs in accelerated hypertension), and edematous disorders (eg, heart failure, cirrhosis with ascites and nephrotic syndrome).
The mineralocorticoid receptor antagonists, also known as aldosterone antagonists, are a known class of drugs which antagonize the action of aldosterone at mineralocorticoid receptors. Antagonism of these receptors inhibits sodium resorption in the collecting duct of the nephron in the kidneys. This inhibits sodium/potassium exchange, reducing urinary potassium excretion and weakly increasing water excretion. This diuretic activity reduces edema and blood pressure. As a consequence, this group of drugs is often used for the treatment of primary hyperaldosteronism and edematous conditions including congestive heart failure, cirrhosis of the liver accompanied by edema and/or ascites, the nephrotic syndrome, essential hypertension and hypokalemia. In addition, mineralocorticoid receptor antagonist has anti-inflammatory and anti-fibrotic effects which are independent of blood pressure lowering effects. Treatment of mineralocorticoid receptor antagonist has shown beneficial effects in Chronic Kidney Disease (Cortinovis et. al., Ther Adv Cardiovasc Dis 2009; 3:133-43), End Stage Renal Disease (Taheri S et. al., Saudi J Kidney Dis Transspl 2009; 79: 863-9), arthritis (Syngle A et. al, Scand J Rheumatol, 2009; 38:15-22), atherosclerosis (Takai S et. al, Hypertension, 2005; 46:1135-39), and stroke (Osmond J M et. al., Clin Sci, 2008; 114: 37-47).
Members of the class of mineralocorticoid receptor or aldosterone antagonists which are currently marketed for clinical use include spironolactone and eplerenone. Spironolactone is actually a prodrug which produces canrenone as an active first metabolite. The latter is not marketed for clinical use.
A number of marketed dihydropyridine calcium channel blockers have also been noted to have mineralocorticoid receptor antagonist activity. (Dietz et al., Hypertension, 2008; 51:742-748)